The critical role of the intrauterine environment on neurodevelopment including mental disease risk is becoming increasingly clear, although the mechanisms through which this environment contributes to psychopathology is certainly complex and not well understood. Our work is beginning to demonstrate the fundamental functional role that the placenta, acting as a master regulator of the intrauterine environment and sharing integrated endocrine control with the brain, can play on neurodevelopment. This preliminary work has compelled this examination, which, in line with the strategic mission of the NIMH, aims to provide critical insights into the mechanisms through which the earliest of life's experiences in the intrauterine environment can, through modification of the epigenome, alter neurodevelopmental pathways and contribute to later mental health disorders. The proposed study is compelled by the hypothesis that the pattern of DNA methylation in the placenta acts to alter the function of the placenta as regulator of the intrauterine environment and thus will be associated with infant neurodevelopment in ways that relate to the later development of psychopathology. We propose a multi-modal, translational research approach, utilizing the population resources of an existing, ongoing population-based birth cohort, the validated, prospective, functional infant neurobehavioral assessments using the NICU Network Neurobehavioral Scale (NNNS), and state-of-the-art approaches for the examination of epigenetic and epigenomic profiles in human samples. The aims of this project are (1) to identify the association between DNA methylation of candidate genes in the placenta and neurobehavioral outcomes at birth using the NNNS (2) to test the hypothesis that profiles of gene-specific DNA methylation of autosomal loci in placenta are associated with neurobehavioral outcomes at birth using the NNNS and to validate these associations, and (3) to test the hypothesis that profiles of gene-specific DNA methylation of sex-linked loci in a sex-stratified manner are associated with neurobehavioral outcomes at birth using the NNNS. The results of this study have the potential to expand our understanding of the developmental origins of mental health, and demonstrate the key role of the placenta and the epigenetic control of its genome in infant neurodevelopment. Identification of an epigenetic signature associated with altered behavioral trajectories in an accessible tissue, such as the placenta, can have significant clinical and public health implications, providing an opportunity for early diagnostic tools which can direct targeted and early interventions for at-risk children. PUBLIC HEALTH RELEVANCE: This research aims to identify the molecular mechanisms through which the effects of the maternal environment elicit lifelong effects on mental health in the newborn child. This work can provide potential avenues for prevention and targeted intervention through the identification of these molecular alterations.